Supramolecular catalysis of a unimolecular transformation: Aza-Cope rearrangement within a self-assembled host

Article abstract of DOI:10.1002/anie.200461776

Catalytic containers: A supramolecular metal-ligand assembly [M ₄L₆] is utilized as a catalytic host for the unimolecular carbon-carbon bond-forming rearrangement of enammonium cations (see scheme). The restricted reaction space of the supramolecular structure forces the substrate to adopt a reactive conformation upon binding to the interior. The assembly achieves up to 850-fold rate acceleration of the rearrangement.

Full text of DOI:10.1002/anie.200461776

Communications
Host–Guest Systems
development of container-like molecules into chemically
useful structures is an attractive goal, and their utilization as
catalytic reaction chambers can parallel the enzyme function.
The rate for a bimolecular Diels–Alder reaction, for example,
was reported to be significantly accelerated in the presence of
a supramolecular host, owing to the increase of effective
concentrations of the two substrates when bound within the
same capsule.[7,8] Major challenges are a) to develop supra-
molecular systems capable of catalyzing unimolecular reac-
tions, and b) to circumvent catalyst inhibition, a problem that
frequently occurs when the cavity binds the reaction product
more strongly than the substrate.[7,9] We report herein the
utilization of a supramolecular metal–ligand assembly that is
capable of catalyzing a unimolecular rearrangement. Simply
by inclusion into a size- and shape-constrained reaction space
these rearrangements are accelerated by up to three orders of
magnitude compared to their background rates. Furthermore,
the chemical properties of the reacting system provide an
effective means of preventing product inhibition, which
facilitates catalyst turnover.
Supramolecular Catalysis of a Unimolecular
Transformation: Aza-Cope Rearrangement
within a Self-Assembled Host**
Dorothea Fiedler, Robert G. Bergman,* and
Kenneth N. Raymond*
Chemists have long envied the ability of enzymes to
manipulate reaction energetics and specificity through steric
confinement and precise functional-group interactions. The
enormous rate accelerations that enzymes achieve at modest
temperatures may be attributed to their high degree of
complexity, and the synthetic chemist is hard pressed to create
such well-constructed catalytic scaffolds. Yet in this regard,
the utilization of supramolecular chemistry may have an
advantage: supramolecular self-assembly facilitates the cre-
ation of large, complex structures from relatively simple
precursors.[1,2] Based on reversible weak interactions, such as
hydrogen bonding or metal–ligand interactions, synthetic
chemists have generated an array of self-assembled struc-
tures, diverse in architecture and composition. Some of these
synthetic structures bear an internal cavity, and their interior
can provide a new and very specific chemical environment,
distinctly different from the exterior surroundings.[3–6] The
Raymond and co-workers have composed supramolecular
tetrahedral structures of M4L6 stoichiometry through self-
assembly of simple metal and ligand components.[10,11] In
these assemblies the metal atoms are located at the vertices of
the tetrahedron and six bis-bidentate catechol amide ligands
span the edges (Figure 1). The tris-bidentate chelation of the
metal centers renders them chiral (D or L), and the
Figure 1. Left: A schematic view of the [GꢀM4L6] (G=guest) supramolecular tetrahedral assembly, looking down the C3-axis. For clarity only one
ligand is drawn, the other ligands are represented as sticks. Middle: CAChe model of [NPr4ꢀFe4L6]11À, the guest molecule is shown in a space-fill-
ing view, the hydrogen atoms are omitted for clarity. Right: The same CAChe model as in the middle, now with host and guest in space filling
view. This representation shows that the guest molecule is not exposed to the assembly exterior, but rather is tightly surrounded by the host.
[*] D. Fiedler, Prof. R. G. Bergman, Prof. K. N. Raymond
mechanical coupling through the rigid ligands results in the
Department of Chemistry
University of California
Berkeley, CA 94720-1460 (USA)
Fax: (+1)510-642-7714 (Bergman)
formation of exclusively homochiral assemblies (i.e. D,D,D,D
or L,L,L,L). By virtue of the 12À overall charge, the
assemblies are water soluble, yet they contain a flexible
hydrophobic cavity of 350–500 ꢀ3 into which they can bind a
Fax: (+1)510-486-5283 (Raymond)
broad range of monocationic guest molecules, from alkyl
E-mail: bergman@cchem.berkeley.edu
raymond@socrates.berkeley.edu
ammonium cations to half-sandwich complexes.[12,13]
[**] Supported by the Director, Office of Energy Research, Office of Basic
Energy Sciences, Chemical Sciences Division, of the U.S. Depart-
ment of Energy under contract DE-AC03-7600098. The authors
would like to thank Prof. David E. Wemmer, Dr. Anna V. Davis,
Dennis H. Leung, and Emily A. Dertz for helpful discussions and
suggestions, Dr. Herman van Halbeek for assistance with the 2D
NMR spectroscopy, and Mathew E. Bishop for creation of the cover
art.
In pursuing supramolecular catalysis, a chemical trans-
formation of a cationic substrate, which is compatible with the
supramolecular host, needed to be identified. The cationic 3-
aza-Cope rearrangement seemed to be the ideal reaction to
be carried out in the finite environment of the M4L6 assembly.
The substrates are ammonium cations (A) and should bind to
the cavity interior (Figure 2, top). Sigmatropic rearrangement
leads to an iminium cation (B), which is subsequently hydro-
lyzed to the corresponding g,d-unsaturated aldehyde (C).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200461776
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Angewandte
Chemie
the rates of rearrangement were measured for the free and
encapsulated enammonium cations. All rearrangements dis-
played clean first-order kinetics in buffered solution at 508C.
Remarkably, the encapsulated substrates rearranged faster in
all cases (Table 1). Substrate 3, for instance, experienced 141-
fold rate acceleration, once encapsulated by the supramolec-
ular assembly. Even more dramatic is the effect on the
isopropyl substituted enammonium cation 7; binding into the
host cavity resulted in a rate increase by a factor of 854.
Control experiments with the free rearrangement showed no
significant solvent dependence, excluding the possibility that
the observed rate enhancement is simply due to the cavityꢁs
more hydrophobic environment. The prospect that the host-
assemblyꢁs negative charge causes the rate acceleration was
ruled out by adding salt (2m KCl) in the absence of the
assembly, which did not result in a significant change in rate
for the free rearrangement.
To elucidate the origin of the observed rate accelerations,
the activation parameters were measured. The obtained
parameters for the free rearrangement of substrate 3, for
example, are DH° = 23.1(Æ 0.8) kcalmolÀ1 and DS° = À8
(Æ 2) e.u. (1 e.u. = 4.184 JKÀ1 molÀ1). These values compare
well with those reported for similar systems,[14] and the
negative entropy of activation reflects the highly organized,
chairlike transition state required for the rearrangement
reaction. The reaction of the encapsulated substrate
[3ꢀGa4L6]11À gave a very similar value for the enthalpy of
activation, DH° = 23.0(Æ 0.9) kcalmolÀ1. The entropy of acti-
vation, however, differs remarkably by almost 10 e.u., with
DS° = +2(Æ 3) e.u. (see Supporting Information). Compara-
ble effects are observed for the other substrates.[15]
Figure 2. Top: A general reaction scheme of the 3-aza-Cope rearrange-
ment. Starting from the enammonium cation A, [3,3] sigmatropic rear-
rangement leads to iminium cation B, which then hydrolyzes to the
aldehyde, C. Bottom: 1H NMR spectrum of [1ꢀGa4L6]11À (1: R1, R2,
R3 =H). The observed upfield shift of guest resonance signals illus-
trates the close contact between host and guest.
Since neutral molecules are only very weakly bound by the
supramolecular host, binding of more substrate could occur
after the hydrolysis step, enabling catalytic turnover.
We explored a range of enammonium substrates A,
diverse in size, shape, and substitution pattern (Table 1). All
These results imply that the host-assembly selectively
binds a reactive conformation of the substrate. The space-
restrictive host cavity only allows
encapsulation of a tightly packed
Table 1: Rate constants for free (kfree) and encapsulated (kencaps) rearrangements (measured at 508C) and
conformation, closely resembling
the conformation of the chairlike
transition state. The predisposed
conformers, which have already
lost several rotational degrees of
freedom, are selected from an
equilibrium mixture of all possible
conformers. Thus the entropic bar-
rier for rearrangement decreases.
This effect of preorganization
becomes more significant for the
larger substrates, which fit more
tightly in the host cavity. For exam-
ple, while an isopropyl substituent
at R2 slows down the rate of the
their acceleration factors.
Substrate
R1
R2
R3
kfree [ꢀ10À5 sÀ1
]
kencaps [ꢀ10À5 sÀ1
]
Acceleration
1
2
3
4
5
6
7
H
Me
H
H
H
H
H
Et
H
nPr
H
H
H
H
Et
H
3.49
7.61
3.17
1.50
4.04
1.69
0.37
16.3
198
446
135
604
74.2
316
5
26
141
90
150
44
854
H
H
nPr
H
iPr
of the substrates were encapsulated by the metal–ligand
assembly, which can most easily be monitored by H NMR
free reaction relative to that of the other substrates, the
bulkier R2 group effects the largest observed acceleration of
the encapsulated reaction. Presumably in free substrate 7 the
additional steric repulsion between the ends of the alkyl
chains reduces the percentage of reactive conformations in
free solution even further, therefore decreasing the rate of
rearrangement. The encapsulated 7, however, does not
display a similar effect; once squeezed into the cavity, the
two pendant alkyl chains are forced to be in close proximity,
1
spectroscopy. Shielding by the naphthalene moiety of the
ligand scaffold causes an upfield shift of the guest resonances
by d = 2–3 ppm. Enammonium cation 1 (R1, R2, R3 = H), for
example, quantitatively yielded the host–guest complex
[1ꢀGa4L6]11À as confirmed by NMR spectroscopy (Figure 2,
bottom) and ES-mass spectrometry. To investigate whether
the substrateꢁs reactivity has been altered by encapsulation,
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and the reaction proceeds at a rate
comparable to those of the other
encapsulated substrates.
The effect of preorganization into
a reactive conformation in the host–
guest system is supported by the 2D
NOESY spectrum of [3ꢀGa4L6]11À
(Figure 3). While the unbound sub-
strate shows no NOEs between the
pendant alkyl chains, the encapsu-
lated enammonium cation displays
strong dipolar couplings between pro-
tons at the two distal ends of the
molecule. Assuming a tight, chairlike
conformation of the bound substrate,
these
correlations
would
be
expected.[16]
It is of interest to compare our
results with the observations on the
enzyme chorismate mutase, which
catalyzes the unimolecular Claisen
rearrangement from chorismate to
prephenate, achieving rate accelera-
tion of a factor of 106 relative to the
uncatalyzed reaction. Even though
this highly complex process is not
fully understood, the factors respon-
sible for the enzymeꢁs catalytic effi-
ciency include reduction of both the
enthalpic and entropic barrier for
rearrangement.[17] It is proposed that
a series of functional groups located at
the active site stabilize the charge
build-up in the transition state, which
causes a decrease in enthalpy of
activation.[18] In addition, the enzyme
binds the substrate in a diaxial, reac-
tive conformation, which lowers the
entropy of activation by 11–
Figure 3. The 2D NOESY spectrum of [3ꢀGa4L6]11À in a D2O/MeOD mixture (70:30) recorded at
À108C, mixing time 100 ms. Indicated in red are selected NOEs. The correlation between Me and
Me at the two distal ends of the molecule demonstrates the cavity’s enforcement of a compressed
and folded guest conformation. Hn =naphthyl protons, Hc =catechol protons.
13 e.u.[19–21] Theoretical studies by Bruice and co-workers on
the chorismate rearrangement imply that the efficiency of
forming near attack conformers (NACs) in the ground state
can be a very important kinetic contribution.[22,23]
idea of the supramolecular assembly providing a catalytic
cavity for rearrangement is further supported by an inhibition
experiment with the very strongly binding guest molecule
[NEt4]+. When eight equivalents of [NEt4]+ were added to the
reaction mixtures to block the host cavity, the catalytic
activity of the supramolecular host was inhibited. Based on
these results, we propose the catalytic mechanism illustrated
in Figure 4: 1) A reactive conformation of the enammonium
cation binds into the restricted space of the host assembly.
2) The rearrangement proceeds with significant acceleration
within the boundaries of the metal–ligand assembly. 3) The
rearranged product equilibrates with the bulk solution, and
hydrolysis to the corresponding aldehyde enables catalytic
turnover by regeneration of the empty assembly that can bind
additional substrate.
Since the enzyme shows such remarkable catalytic proper-
ties, the question arose as to whether the M4L6 supramolec-
ular assembly would also be able to mediate the aza-Cope
rearrangement catalytically. The stoichiometric experiments
had shown that in all cases of the host-mediated 3-aza-Cope
rearrangement, the iminium cations B hydrolyzed rapidly to
the corresponding aldehydes C, leaving behind an empty
cavity.[24] This property should enable the reaction to be
carried out under catalytic conditions. Indeed, carrying out
the reaction in the presence of 13 mol% catalyst relative to
enammonium substrate revealed truly catalytic behavior of
the supramolecular host. Raising the catalyst loading from
13 mol% to 27 mol% to 40 mol% resulted in the expected
increases in rate; the observed initial rate constants at 258C
These findings highlight the ability of container-like
molecules to provide size- and shape-defined nanospaces,
highly capable of catalysis of unimolecular organic reactions.
By binding the substrates in a reactive conformation, the host
assembly accelerates the rates of rearrangement by up to
are
k
k k
13 mol% = 0.64 ꢂ 10À4 sÀ1, 27 mol% = 1.17 ꢂ 10À4 sÀ1, and
40 mol% = 1.80 ꢂ 10À4 sÀ1 (see Supporting Information). The
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Chemie
[4] J. C. Sherman, D. J. Cram, J. Am. Chem. Soc. 1989, 117, 4527.
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[10] D. L. Caulder, K. N. Raymond, Acc. Chem. Res. 1999, 32, 975.
[11] D. L. Caulder, C. Brꢃckner, R. E. Powers, S. Kꢄnig, T. N. Parac,
J. A. Leary, K. N. Raymond, J. Am. Chem. Soc. 2001, 123, 8923.
[12] D. Fiedler, D. H. Leung, R. G. Bergman, K. N. Raymond, J. Am.
Chem. Soc. 2004, 126, 3674.
[13] D. H. Leung, D. Fiedler, R. G. Bergman, K. N. Raymond,
Angew. Chem. 2004, 116, 981; Angew. Chem. Int. Ed. 2004, 43,
963.
Figure 4. Proposed catalytic cycle for the cationic 3-aza-Cope
rearrangement, see text for details.
[14] S. Jolidon, H.-J. Hansen, Helv. Chim. Acta 1977, 60, 978.
[15] D. Fiedler, R. G. Bergman, K. N. Raymond, unpublished results.
[16] The short mixing time of 100 ms ensures that no correlations
resulting from spin diffusion are observed.
three orders of magnitude. Release and hydrolysis of the
rearranged product generate catalytic turnover. With this, the
large potential of supramolecular assemblies as synthetically
useful tools in organic chemistry becomes apparent.
[17] H. Gorisch, Biochemistry 1978, 17, 3700.
[18] A. Kienhofer, P. Kast, D. Hilvert, J. Am. Chem. Soc. 2003, 125,
3206.
[19] A. Y. Lee, J. D. Stewart, J. Clardy, B. Ganem, Chem. Biol. 1995,
2, 195.
Received: August 24, 2004
Published online: November 19, 2004
Keywords: cage compounds · homogeneous catalysis ·
host–guest systems · sigmatropic rearrangement
[20] H. Guo, Q. Cui, W. N. Lipscomb, M. Karplus, Proc. Natl. Acad.
Sci. USA 2001, 98, 9032.
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[21] S. D. Copley, J. R. Knowles, J. Am. Chem. Soc. 1987, 109, 5008.
[22] S. Hur, T. C. Bruice, J. Am. Chem. Soc. 2003, 125, 10540.
[23] T. C. Bruice, F. C. Lightstone, Acc. Chem. Res. 1999, 32, 127. For
[1] J. L. Atwood, J. E. D. Davies, D. D. MacNicol, F. Voegtle, J.-M.
Lehn, Comprehensive Supramolecular Chemistry, Pergamon,
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[2] J.-M. Lehn, Supramolecular Chemistry: Concepts and Perspec-
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ˇ
further discussion, see also: M. Strajbl, A. Shurki, M. Kato, A.
Warshel, J. Am. Chem. Soc. 2003, 125, 10228.
[24] In the experiments reported herein, the empty cavity refers to
the host cavity containing the counterion [NMe4]+. The [NMe4]+
ion has a very weak binding constant and is easily replaced by the
different substrates.
[3] L. Garel, J.-P. Dutasta, A. Collet, Angew. Chem. 1993, 105, 1249;
Angew. Chem. Int. Ed. Engl. 1993, 32, 1169.
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